Cannabis is one of the most widely used psychotropic drugs and it has been linked with numerous serious adverse effects including dependence, psychiatric disorders, and cardio-respiratory disease. Detailed knowledge about the mechanisms by which this drug acts is crucial to understand its many effects, and may greatly assist the design of drugs to facilitate treatment of cannabis dependence and withdrawal. Identification of all the cannabinoid receptors is central to this problem. In addition to the two well-characterized classical cannabinoid receptors three other receptors have recently been identified. Based on its distribution and function in the brain it has also been suggested that the extracellular Ca-sensing receptor (CaSR) would be a suitable target for cannabinoids. In preliminary experiments we found that cannabinoids activate CaSR, a G-protein coupled receptor (GPCR), that is localized in the majority of nerve terminals in the brain, and decreases synaptic transmission when activated. These preliminary findings, coupled with the abundance of CaSR in the brain, may fundamentally change our understanding of the mechanism of action of cannabinoids. The objective of this proposal is to determine if CaSR is an important pathway in the action of cannabinoids and our hypothesis is that brain CaSR is activated directly by cannabinoids. We are ideally suited to perform this project because of our expertise in CaSR function in nerve terminals and expression systems. The sensitivity of CaSR to cannabinoids and the prevalence of CaSR in the brain will open up a new view of cannabinoid action, substantially changing thinking in the field. Successful completion of these specific aims will characterize the response of CaSR to cannabinoids, shedding light on the broader range of influence of CaSR. This work will define the tools necessary to dissect the relative contributions of CaSR and CB1 to cannabinoid modulation of synaptic transmission in the brain. Future proposals would combine pharmacological and genetic approaches to ascertain the impact of cannabinoids via CB1 and CaSR at central synapses. Our rationale is that the identification and characterization of a novel and prevalent cannabinoid receptor will facilitate our understanding of the behavioral actions of the commonly used drug cannabis. Moreover, distinguishing the various actions of cannabinoids may translate into the identification of a novel class of drugs that facilitate treatment of cannabis addiction and withdrawal. PUBLIC HEALTH RELEVANCE: Cannabis is a commonly used drug that is associated with drug dependence and serious psychiatric, cardiovascular and pulmonary diseases. New treatments are needed to help people stop using cannabis but this requires improved understanding of how cannabis works. We have discovered a new pathway in the brain that is activated by cannabis-like drugs. By studying this new pathway we will discover more about how cannabis works and so improve the chances of designing new treatments to help stop cannabis use.